Human liver microsomes are small vesicles derived from the endoplasmic reticulum of liver cells, containing a high concentration of drug-metabolizing enzymes. Their primary role in biomedical research is to serve as a model for studying how the body processes various substances. This makes them a tool in the fields of pharmacology and toxicology.
The use of liver microsomes allows scientists to investigate the metabolic pathways of new chemical compounds in a controlled laboratory setting. This in vitro (in a test tube) system provides insights into how a drug might behave in the human body. These fractions are noted for their stability and ease of use, and can be stored for long periods while retaining enzyme activity, making them a cost-effective and reproducible resource.
Function Within the Body
The primary function of liver microsomes in the body is to carry out Phase I metabolism. This is the initial step in a process called biotransformation, where foreign substances, known as xenobiotics, are chemically altered. These substances include compounds like therapeutic drugs and environmental toxins. The objective of this phase is to make these compounds more polar, or water-soluble, which prepares them for elimination from the body through urine or bile.
This metabolic process is driven by a large family of enzymes called Cytochrome P450 (CYP450). When a xenobiotic enters the liver, CYP450 enzymes catalyze chemical reactions, such as oxidation, reduction, and hydrolysis. These reactions introduce or unmask functional groups on the molecule, which changes the compound’s structure and biological activity.
Beyond their work on foreign chemicals, these same enzyme systems also participate in the metabolism of endogenous compounds, which are substances naturally produced by the body. This includes the synthesis and breakdown of steroid hormones, such as estrogen and testosterone, as well as the processing of fatty acids. The dual role of these enzymes highlights their importance in maintaining normal physiological functions.
Use as a Research Tool
Scientists isolate microsomes from donated human liver tissue to harness the liver’s metabolic power in a lab. The process, known as differential centrifugation, begins with breaking up liver cells to release their internal components. This mixture is then spun in a centrifuge at increasing speeds, separating cellular components by size and density.
This process results in a preparation known as human liver microsomes (HLMs), which create a simplified in vitro system. Using HLMs offers several advantages for research. It allows for the study of metabolic pathways without the complexities and ethical issues of testing in live humans. This model is reproducible, cost-effective, and can be used in high-throughput screening to test many compounds at once, generating reliable data.
Applications in Drug Discovery
In pharmaceutical development, HLMs are used for several specific studies. One primary application is determining metabolic stability. Researchers incubate a drug candidate with HLMs and measure how quickly the compound is broken down by the enzymes. This rate of metabolism helps predict the drug’s half-life in the body, which determines how long it will remain active and how frequently it needs to be dosed.
Another use is for metabolite identification. When a drug is metabolized, it is converted into new molecules called metabolites, which may have their own biological effects or potential toxicities. By analyzing the mixture after an HLM incubation using techniques like mass spectrometry, scientists can identify the structure of these metabolites. This information is used for a comprehensive safety assessment of the drug candidate.
HLMs are also used to study drug-drug interactions (DDIs), which assess if one drug affects another’s metabolism. For instance, a drug might inhibit a CYP450 enzyme, causing a second drug to build up to toxic levels. Conversely, a drug could induce more enzymes, rapidly breaking down a co-administered drug and reducing its effectiveness. These studies are a standard part of preclinical safety evaluation.
Variability in Microsomal Activity
The activity of microsomal enzymes varies considerably between individuals, which has clinical implications. A primary source of this variability is genetics. The field of pharmacogenomics studies how a person’s genetic makeup affects their drug response. Variations in the genes that code for CYP450 enzymes can lead to enzymes with altered function.
These genetic differences categorize people into metabolizer phenotypes. For example, “poor metabolizers” inherit non-functional copies of a CYP gene, leading to slow drug processing. In contrast, “ultra-rapid metabolizers” have gene duplications, causing them to break down certain drugs very quickly. This explains why a standard drug dose might be toxic for one person but ineffective for another.
Beyond genetics, other factors influence microsomal enzyme activity. Liver disease can impair metabolic function, and age plays a role, as metabolic capacity differs in pediatric and elderly populations. Environmental factors like tobacco smoke and lifestyle choices like consuming grapefruit juice can also inhibit or induce specific CYP enzymes. This interplay of factors creates a complex landscape of individual metabolic capability.